Particle formulations for use in pharmaceutical compositions

ABSTRACT

A liquid composition in an osmotic drug delivery system and a dosage form in an osmotic drug delivery system is disclosed comprising an amphiphilic molecule, a non-aqueous liquid solvent, and a pharmaceutically active agent.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.12/655,397, filed on 29 Dec. 2009, now U.S. Pat. No. 7,964,183, which isa continuation of U.S. patent application Ser. No. 10/988,716, filed on15 Nov. 2004, now U.S. Pat. No. 7,731,947, which claims the benefit ofU.S. Provisional Application Ser. No. 60/520,605, filed on 17 Nov. 2003,now expired; and is a continuation-in-part of U.S. patent applicationSer. No. 12/315,194, filed on 26 Nov. 2008, now abandoned, which is acontinuation of U.S. patent application Ser. No. 10/742,730, filed on 19Dec. 2003, now abandoned, which claims the benefit of U.S. ProvisionalApplication Ser. No. 60/435,180, filed on 19 Dec. 2002, now expired; allof which applications are herein incorporated by reference in theirentireties in the present application.

FIELD

The present invention relates to liquid composition in an osmotic drugdelivery system and a dosage form of a liquid composition in an osmoticdrug delivery device.

BACKGROUND

Development of drug suspension formulations designed for delivery fromsustained delivery devices and osmotic delivery devices has resulted ina family of compositions utilizing polymer or surfactant solutions,non-aqueous liquid solvents or blends of solvents for polymer. Thepolymer acts as a viscosity modifier to provide acceptable stability ofthe suspension during self storage and performance intervals. Thesepolymer solutions provide a stable environment for pharmaceuticallyactive agents, e.g., small molecule drugs or therapeutic proteins orpeptides.

Drug delivery devices attempt to deliver low solubility drugs byincorporating liquid drug formulations that are released at a controlledrate over time. These osmotic delivery devices are disclosed in U.S.Pat. Nos. 4,111,201; 5,324,280; 5,413,672; and 6,174,547. However, suchliquid osmotic delivery systems are limited in the concentration of drugin the liquid formulation and hence, the drug loading available, leadingto delivery systems that can be of an unacceptably large size, volume,or number for therapeutic purposes.

Polymers, such as polyvinyl pyrrolidone (PVP), exhibit solubility in awide range of non-aqueous liquid solvents, but PVP is also quite solublein water. As a result, highly viscous PVP/water gels can be producednear the formulation/water interface. These viscous gels can occlude thedelivery conduit of the drug delivery device, interfering withperformance of the delivery device. A need exists in the art to developa viscous liquid compositions with improved performance characteristicsin drug delivery devices, for example, osmotic drug delivery devices.There also exists a need to eliminate pluggage of discharge ports ofimplantable devices. Additionally, there is a need for suspendingvehicles that are substantially resistant to phase separation while atthe same time are sufficiently viscous to suspend pharmaceutical agentsfor long periods of time. Further, it is desirable to formulatepolymer-free dosage forms which remain substantially homogenous for adesired dosaging time.

SUMMARY

The invention is generally related to drug delivery compositionscomprising amphiphilic molecules in combination with a solvent formliquid compositions with desired properties that exhibit a desiredviscosity and that exhibit a desired solvency in water. The viscousliquid compositions are useful for therapeutic drug deliveryapplications in which the formulation can be slowly introduced into anaqueous environment.

In one embodiment, a liquid composition in an osmotic drug deliverysystem comprises an amphiphilic molecule, a non-aqueous liquid solvent,and a pharmaceutically active agent. In a further embodiment,amphiphilic molecules include, but are not limited to, lipids,surfactants, amphiphilic block polymers, or amphiphilic proteins orpeptides. In a further detailed embodiment, the lipid is selected fromsaturated lipid, unsaturated lipid, neutral lipid, anionic lipid,cationic lipid, natural lipid or synthetic lipid.

Amphiphilic molecules, for example, lipids, in combination with asolvent, form a viscous liquid formulation that exhibits a desiredsolvency in water for drug delivery applications in which theformulation is slowly introduced into an aqueous environment.Amphiphilic molecules, such as lipids, in non-aqueous liquid solventscan provide viscous liquid compositions for therapeutic drug or proteindelivery in a system or delivery device that avoids problems ofprecipitation, aggregation, or formation of highly viscous gels at thelipid/solvent/water interface. The liquid composition overcomes problemswhich can limit delivery of a therapeutic composition from the deliverydevice. Amphiphilic molecules, such as lipids, in non-aqueous liquidsolvents deliver therapeutic drugs or proteins from a delivery deviceinto an aqueous environment in a continuous measured flow to the targettissue of interest.

Amphiphilic molecules, e.g., lipids in non-aqueous liquid solvents, canreplace delivery systems comprising high molecular weight molecules,e.g., polymers such as PVP or PLGA, when forming therapeutic drugdelivery systems in which particular rheological properties are desired.When introduced into an aqueous environment, lipids can be amphiphilicmolecules capable of forming small self-assembled structures in waterwith forms ranging from bi-layers (multilamellar vesicles, unilamellarvesicles/liposomes) to micelles and even inverted micelles (hexagonalstructure).

Drug delivery compositions comprising lipids in non-aqueous liquidsolvents have been formulated into stable suspensions of a therapeuticdrug suitable for dispensing from osmotic delivery devices for extendedintervals. Compositions comprising lipids and non-aqueous liquidsolvents can exhibit a variety of solubility properties in water andfurther can exhibit significant partitioning of the lipids at a waterinterface resulting in viscous liquid compositions e.g., viscous lipidgels.

In a further embodiment, drug delivery compositions comprising lipids innon-aqueous liquid solvents have been formulated into stable suspensionswherein the pharmaceutically active agent is suspended in a particlewithin said liquid composition. The particles containing thepharmaceutically active agent can be formed by a number of differentprocesses, e.g., spray drying, lyophilization, or supercritical fluidprocessing.

In a detailed embodiment, non-aqueous liquid solvents useful to producesuch gels include, but are not limited to, lauryl lactate (LL), laurylalcohol (LA), benzyl alcohol (BA), benzyl benzoate (BB), 1:1 benzylbenzoate: benzyl alcohol, benzyl alcohol, ethyl hexyl lactate, glycerolformal, tetraglycol (glycofurol; GF), N-1-methyl-2-pyrrolidone (NMP),dimethyl sulfoxide, (DMSO), polyethyleneglycol (e.g., PEG 400),triglycerides (triolein, trilaurin, tricarprin, tricaprylin), ethanol,isopropanol, t-butyl alcohol, cyclohexanol, glycerin, glycerol,α-tocopherol (vitamin E) vegetable oil, sesame oil, soybean oil,cottonseed oil or peanut oil.

Various amphiphilic molecules can be used, e.g., lipids, surfactants,amphiphilic block polymers, or amphiphilic proteins or peptides. Lipidmolecules include, but are not limited to, saturated and unsaturatedlipids; neutral, cationic, or anionic lipids; or natural or syntheticlipids. Anionic lipids can induce formation of a helical segment of aprotein, and can play an important physiological role. In a detailedembodiment, lipids can be one or a mixture of two or more from any ofthe following classes including, but not limited to: phosphatidylcholine(PC), phosphatidylethanolamine (PE), phosphatidylglycerol (PG),phosphosphatidylinositol (PI), phosphatidylserine (PS), phosphatidicacid (PA) sphingomyelin (SM).

In a detailed embodiment, individual lipids include, but are not limitedto: neutral lipids—dioleoyl phosphatidylcholine (DOPC),dimyristoylphosphatidylcholine (DMPC), dipalmitoylphosphatidylcholine(DPPC), distearoylphosphatidylcholine (DSPC), egg phosphatidylcholine(egg PC), soy phosphatidylcholine (soy PC), partially or fullyhydrogenated phosphatidylcholines (PHSPC or HSPC), palmitoyl-oleoylphosphatidylcholine (POPC), stearyloleoylphosphatidylcholine (SOPC); andanionic lipids—dioleoy phosphatidylglyserol (DOPG),dimyristoylphosphatidylglycerol (DWG), dipalmitoylphosphatidylglyserol(DPPG), distearoylphosphatidylglyserol (DSPG). Various PEG (polyethyleneglycol)-lipids can also be included for added benefit. Examples ofPEG-lipids include, but are not limited to mPEG-DPPE, mPEG-DMPE,mPEG-DSPE, -mPEG-ceramide-DSPE, or mPEG-DS. Block copolymer surfactants(e.g., Pluronic® surfactants or Pluronic® surfactant F-127), or sorbitanesters structurants (e.g., Span® 80, Sigma Aldrich Chemical Co.) can beused. Moreover, when needed, increments of anti-oxidant lipid agentsincluding, but not limited to, vitamin E, α-tocopherol, or ascorbicacid, can be added to prevent oxidation or peroxide formation. Theincrements of anti-oxidant lipid agents are already a part of the PHSPCformulations.

Amphiphilic molecule weight percent in the formulation can range fromabout 1 to about 100 weight percent, in detailed embodiments. Solventweight percent in the formulation can range from about 0 to about 99weight percent.

In a further embodiment, the pharmaceutically active agent is selectedfrom a protein, peptide, small molecule drug, lipid drug or nucleic aciddrug (e.g., DNA, RNA, antisense, ribozyme, DNAzyme, and the like).

The liquid composition is a viscous liquid composition, in a furtherdetailed embodiment. The viscosity of the composition can be from about1 to about 100,000 poise. A ratio by weight of amphiphilic molecule tonon-aqueous liquid solvent can be between about 1 and about 4.

In a further embodiment, the pharmaceutically active agent is selectedfrom biologically or pharmacologically active substance. In a detailedembodiment, the pharmaceutically active agent is ω-interferon,α-interferon, β-interferon, γ-interferon, erythropoietin, human growthhormone, granulocyte macrophage colony stimulating factor (GM-CSF),human growth hormone releasing hormone (huGHRH), insulin, desmopressin,infliximab, antibody or an agent conjugated to a targeting ligand,risperidone, paliperidone, glucagon-like peptide-1 (GLP-1), or bonemorphogenic protein. The pharmaceutically active agent can be combinedwith sucrose, methionine and citrate in weight ratios of 1 to 2 to 1 to2.15.

In another embodiment, a dosage form for osmotic drug delivery comprisesa capsule including a first chamber containing a viscous liquidpharmaceutical composition and a second chamber containing an osmoticagent, the first chamber having an opening through which thepharmaceutical composition can be delivered from the first chamber to alocation external of the first chamber; a movable separating memberpositioned in the capsule between the first chamber and the secondchamber; a wall of the second chamber including a fluid permeableportion allowing fluid to pass from a surrounding environment into thesecond chamber; and an incompressible fluid additive located within thesecond chamber and substantially surrounding the osmotic agent.

In a detailed embodiment of the dosage form for osmotic drug delivery,the viscous liquid pharmaceutical composition comprises an amphiphilicmolecule, a non-aqueous liquid solvent, and a pharmaceutically activeagent. In a further detailed embodiment, the amphiphilic molecule isselected from lipids, surfactants, amphiphilic block polymers, oramphiphilic proteins or peptides.

In a detailed embodiment of the dosage form for osmotic drug delivery,the lipid is selected from saturated lipid, unsaturated lipid, neutrallipid, or anionic lipid. In a further detailed embodiment, the lipid isselected from phosphatidylcholine (PC), phosphatidylethanolamine (PE),phosphatidylglycerol (PG), phosphosphatidylinositol (PI),phosphatidylserine (PS), phosphatidic acid (PA), or sphingomyelin (SM).In a further detailed embodiment, the neutral lipid is selected fromdioleoyl phosphatidylcholine (DOPC), dimyritoylphosphatidylcholine(DMPC), dipalmitoylphosphatidylcholine (DPPC),distearoylphosphatidylcholine (DSPC), egg phosphatidylcholine (egg PC),soy phosphatidylcholine (soy PC), partially or fully hydrogenatedphosphatidylcholins (PHSPC or HSPC), palmitoyl-oleoylphosphatidylcholine (POPC), or stearyloleoylphosphatidylcholin (SOPC).In a further detailed embodiment, the anionic lipid is selected fromdioleoy phosphatidylglycerol (DOPG), dimyritoylphosphatidylglycerol(DMPG), dipalmitoylphosphatidylglycerol (DPPG), ordistearoylphosphatidylglycerol (DSPG).

In a detailed embodiment of the dosage form for osmotic drug delivery,the non-aqueous liquid solvent is selected from lauryl lactate (LL),lauryl alcohol (LA), benzyl alcohol (BA), benzyl benzoate (BB), 1:1benzyl benzoate: benzyl alcohol, benzyl alcohol, ethyl hexyl lactate,glycerol formal, tetraglycol (glycofurol; GF), N-1-methyl-2-pyrrolidone(NMP), dimethyl sulfoxide, (DMSO), polyethyleneglycol (e.g., PEG 400),triglycerides (triolein, trilaurin, tricarprin, tricaprylin), ethanol,isopropanol, t-butyl alcohol, cyclohexanol, glycerin, glycerol,α-tocopherol (vitamin E) vegetable oil, sesame oil, soybean oil,cottonseed oil or peanut oil.

The pharmaceutically active agent is selected from a protein, peptide,small molecule drug, lipid drug or prodrug conjugated to lipid, in afurther embodiment.

An amphiphilic molecule weight percent can be from about 1 to about 100weight percent, in a detailed embodiment of the dosage form for osmoticdrug delivery. In a further detailed embodiment, a non-aqueous liquidsolvent weight percent can be from about 0 to about 99 weight percent.In further detailed embodiments, viscosity of the composition can befrom about 1 to about 100,000 poise. A ratio by weight of amphiphilicmolecule to non-aqueous liquid solvent can be between about 1 and about4.

The osmotic agent is in a tabular form and the fluid additive surroundsthe tabular osmotic agent, in a detailed embodiment of the dosage formfor osmotic drug delivery. The separating member can be a slidablepiston. The fluid permeable portion can be a membrane. In a furtherdetailed embodiment, the osmotic agent is a tablet. The fluid additivecan be a lubricating liquid for preventing freeze-up of the osmoticagent. The fluid additive can be a gel. In a further detailedembodiment, the fluid additive includes PEG. The osmotic agent includesNaCl.

In a detailed embodiment, the dosage form for the osmotic drug deliverysystem includes at least one gap between an inner surface of the capsuleand the osmotic agent, the fluid additive filling the at least one gapto improve start-up time.

In a further aspect, the present invention provides suspending vehiclesthat comprise a amphiphilic molecule, a non-aqueous solvent, and aperformance modifier. Preferably the suspending vehicles aresubstantially non-aqueous. Amphiphilic molecules can replace polymers insuspending vehicles in order to build viscosity. Performance modifiersin accordance with the present invention can be used, for example, toimprove the stability and/or the flowability of lipid-based suspendingvehicles. For example, the use of performance modifiers aids insoftening formations, for example, stiff gels, made at exit ports uponcontact by the suspending vehicle with aqueous media, for example,bodily fluids. As such, suspending vehicles are preferably flowable uponcontact with an aqueous medium. Suspending vehicles are alsosubstantially free of stiff gels upon contact with an aqueous medium.

Another benefit to using performance modifiers, such as co-solvents, isto speed-up preparation of suspending vehicles and suspensions due toincreased solubility of the amphiphilic molecule, for example, thelipid, in co-solvents relative to another solvent.

Suspending vehicles comprising performance modifiers can exhibitimproved rheological properties as compared to suspending vehicles whichdo not contain the performance modifier. For example, performancemodifiers can be useful for reducing viscosity variations over smallcomposition variations. In a preferred embodiment, the suspendingvehicle has a change in viscosity of less than or equal to a factor of10 in combination with a 10% by weight change in amount of theamphiphilic molecule in the suspending vehicle.

In some embodiments, the amphiphilic molecule in the suspending vehiclepreferably comprises a phospholipid. Lipids include, but are not limitedto, dioleoyl phosphatidylcholine (DOPC), dimyritoylphosphatidylcholine(DMPC), dipalmitoylphosphatidylcholine (DPPC),distearoylphosphatidylcholine (DSPC), egg phosphatidylcholine (egg PC),soy phosphatidylcholine (soy PC), partially hydrogenatedphosphatidylcholins (PHSPC), fully hydrogenated phosphatidylcholins(HSPC), palmitoyl-oleoyl phosphatidylcholine (POPC), orstearyloleoylphosphatidylcholine (SOPC).

Suspending vehicles have a weight ratio of the non-aqueous solvent tothe performance modifier that is, for example, preferably from about 1:3to about 1:0.001, more preferably from about 1:1 to about 1:0.001, andeven more preferably from about 1:0.33 to about 1:0.001. A weight ratioof the amphiphilic molecule to the performance modifier is preferablyfrom about 0.18:1 to about 5.7:1, more preferably from about 0.43:1 toabout 2.33:1, and even more preferably from about 0.67:1 to about 1.5:1.A weight ratio of the amphiphilic molecule to a combination of theperformance modifier and the non-aqueous solvent is preferably fromabout 0.05:1 to about 19:1, more preferably from about 0.5:1 to about1.5:1, even more preferably from about 0.75:1 to about 1.22:1.

In a preferred embodiment of a suspending vehicle, the lipid comprisesdioleoyl phosphatidylcholine (DOPC), the non-aqueous solvent comprisesα-tocopherol, and the performance modifier comprises ethanol, sesameoil, ethyl acetate, or combinations thereof.

Kits in accordance with the present invention comprise a suspendingvehicle and instructions for suspending or dispersing a pharmaceuticallyactive agent therein to create a pharmaceutical suspension. Other kitsfurther comprise a dosage form and instructions for loading the dosageform with the pharmaceutical suspension.

Pharmaceutical suspensions can be created by adding a pharmaceuticallyactive agent to suspending vehicles of the present invention.Pharmaceutical suspensions can also be added to desirable dosage forms,for example, dosage forms that are driven by pumps, for example, osmoticdelivery devices.

Pharmaceutical suspensions in accordance with the present inventioncomprise a pharmaceutically active agent suspended or dispersed in asuspending vehicle, wherein the suspending vehicle comprises anamphiphilic molecule, a non-aqueous solvent, and a performance modifier.Suspending vehicles have a viscosity of from about 1 to about 1,000,000poise, preferably the viscosity is from about 5 to about 100,000 poise.

Although any desirable pharmaceutically active agent may be stable inthe suspending vehicles of the present invention, in preferredembodiments, the pharmaceutically active agent comprises ω-interferon.

Preferably, the dosage forms used in conjunction with the presentinvention have an osmotic pump. In other embodiments, the dosage formscomprise a wall that maintains its physical and chemical integrityduring the life of the dosage form and is substantially impermeable to apharmaceutical suspension; another wall that is partially permeable toan exterior fluid; a compartment defined by the wall; and an exit portin the wall in communication with the compartment; and wherein thepharmaceutical suspension is positioned within the compartment.

In some examples, the pharmaceutical suspension is flowable through theexit port upon contact with an aqueous medium, preferably under normaloperating conditions of the osmotic pump. The pharmaceutical suspensionscan also be substantially free of stiff gels upon contact with anaqueous medium. In other embodiments, the pharmaceutical suspensions aresubstantially homogeneous for at least 3 months.

Kits in accordance with the present invention comprise a dosage formcontaining a pharmaceutical suspension and instructions foradministering the dosage form.

Methods in accordance with the present invention comprise identifying anamphiphilic molecule; identifying a non-aqueous solvent; identifying aperformance modifier; mixing the amphiphilic molecule, the non-aqueoussolvent, and the performance modifier to create a suspending vehicle. Insome embodiments, the performance modifier improves rheologicalproperties of the suspending vehicle as compared to a suspending vehiclewhich does not contain the performance modifier. Other methods includesubstantially dissolving or dispersing the amphiphilic molecule in theperformance modifier to create a mixture; and combining the non-aqueoussolvent with the mixture to create a suspending vehicle. Additionally,in other methods, the amphiphilic molecule dissolves more quickly in acombination of the non-aqueous solvent and the performance modifier ascompared to dissolution in only the non-aqueous solvent.

In some methods, the mixture is vortexed. In other embodiments, it ispreferable to heat the suspending vehicle to a temperature of from about100° C. to about 120° C.

Methods in accordance with the present invention also includeadministering the dosage form containing pharmaceutical suspensions inaccordance with the present invention to a mammal.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows that DOPC formulations can be shear thinning, a phenomenathat can ease the manufacturing process of the vehicles.

FIG. 2 shows that the viscosity of DOPC formulations is temperaturecontrolled.

FIG. 3 shows that PHSPC formulations can be shear thinning, a phenomenathat can ease the manufacturing process of the vehicles.

FIG. 4 shows that the viscosity of PHSPC formulations is temperaturecontrolled.

FIG. 5 shows images of DOPC formulations under polarized microscopy.

FIG. 6 shows images of PHSPC formulations under polarized microscopy.

FIG. 7 shows a shear rate effect on a DOPC:LL vehicle formulation at 37°C.

FIG. 8 shows a shear rate effect on a DOPC:NMP vehicle formulation at37° C.

FIG. 9 shows the stability of ω-interferon in DOPC:LL suspension at 40°C.

FIG. 10 shows the effect of n-propanol on recovery of ω-interferon fromDOPC:NMP or DOPC:LL suspensions.

FIG. 11 shows water ingress into model diffusion moderators for viscousliquid formulations, DOPC:LL or DOPC:NMP.

FIG. 12 shows a measure of the average protein released from a deliverydevice based on piston movement within the device.

FIG. 13 shows piston movement in a delivery device correlates to theaverage protein released from the device.

FIG. 14 shows viscosities of various DOPC:VitE formulations at variousweight ratios.

DETAILED DESCRIPTION

A liquid composition in an osmotic drug delivery system of the presentinvention comprises amphiphilic molecules in combination with a solventto form liquid compositions with desired properties that exhibit adesired viscosity and that exhibit a desired solvency in water. Theviscous liquid compositions are useful for therapeutic drug deliveryapplications in which the formulation is slowly introduced into anaqueous environment. Amphiphilic molecules include, but are not limitedto, lipids, surfactants, amphiphilic block polymers, or amphiphilicproteins or peptides.

Dynamic transfer mechanisms occur at the interface between non-aqueousliquid viscous drug suspensions as they pass through a conduit of a drugdelivery device into an aqueous environment. Water ingress into theconduit can occur by one or all of several potential mechanisms: backdiffusion, partitioning or percolation through the packed particles ofthe dispersed phase. Lipids exhibit solubility or dispersion in a widerange of non-aqueous liquid solvents. The wide range of solubility ordispersity lends to the use of lipids in formulation of viscous liquiddrug compositions. When the viscous liquid composition contacts theaqueous environment, lipids can form small vesicles of one or allseveral potential forms: bilayers (multilamellar vesicles, unilamellervesicles/liposomes), micelles or inverted micelles (hexagonal structure)in water. This self-assembly characteristic allows for viscous deliveryvehicles to be formed while at the same time limiting precipitation orthe formation of highly viscous materials at the formulation/waterinterface.

Polymers, for example PVP, exhibit solubility in a wide range ofnon-aqueous liquid solvents as well, but they can also be quite solublein water. As a result, highly viscous PVP/water gels can be produced inthe non-aqueous liquid solvent/water interface. These viscous gels canocclude the delivery conduit, interfering with performance of thedelivery device. In addition, while polymer gels form in the diffusionmoderator of DUROS osmotic drug delivery system, they can precipitateand plug a conduit of the system, thus interfering with the release ofthe drug or therapeutic protein.

Amphiphilic molecules, e.g., lipids, in non-aqueous liquid solvents canprovide liquid viscous drug and protein delivery systems in an osmoticdelivery device. The composition can limit precipitation, aggregation orthe formation of highly viscous gels in the solvent/lipid/waterinterface. Amphiphilic molecules, e.g., lipids, can also provide a lessdetrimental environment to incorporated therapeutic proteins due to theslower uptake of water after administration. Lipids can also be used asstabilizers for proteins to extend the therapeutic efficacy of theprotein drug.

“Non-aqueous liquid solvent” refers to an organic molecule that willform a liquid viscous solution in combination with an amphiphilicmolecule in the absence of water. The solvent can be, for example, anon-polar solvent, a protic solvent, such as an alcohol or acid, or anaprotic solvent, a polar solvent of moderately high dielectric constant,which does not contain an acidic hydrogen.

Lipids can be dissolved in various non-aqueous liquid solvents indifferent ratios to adjust the viscosity of the vehicle from 1-1,000,000poise. These formulations can be shear thinning, a phenomena that canease the manufacturing process of the vehicles. In addition, the solventto be used can be optimized for maximal stability of the protein. Insome cases, both lipids and the solvents to be used in the viscousliquid composition are approved for parenteral use by the Food and DrugAdministration (FDA). Amphiphilic molecule weight percent in theformulation can range from about 1 to about 100 weight %. Solvent weightpercent into the formulation can range from about 0 to about 99 weight%.

The viscous liquid compositions, including a pharmaceutically activeagent cam be delivered by an osmotic drug delivery device, for example,U.S. Pat. Nos. 6,132,420; 6,174,547; 6,419,952; 6,551,613, eachincorporated herein by reference in their entirety.

Viscous liquid compositions can exhibit the desired solvency in waterand can have potential delivery applications in which the formulation isslowly introduced into an aqueous environment. Viscous liquidcompositions comprising lipids in non-aqueous liquid solvents canreplace the use of polymers such as polyvinyl pyrrolidone (PVP) to buildviscosity in suspension vehicles. In an exemplary embodiment of viscousliquid compositions, solvents in which ω-interferon was shown to have asolubility of less than 0.1 mg/mL were combined with the lipid1,2-Dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) to form asuspension of ω-interferon in solid particles in a pharmaceuticalformulation. The exemplary non-aqueous liquid solvents included, but arenot limited to, lauryl lactate (LL), lauryl alcohol (LA), benzyl alcohol(BA), benzyl benzoate (BB), 1:1 benzyl benzoate: benzyl alcohol, benzylalcohol, ethyl hexyl lactate, glycerol formal, tetraglycol (glycofurol;GF), N-1-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide, (DMSO),polyethyleneglycol (e.g., PEG 400), triglycerides (triolein, trilaurin,tricarprin, tricaprylin), ethanol, isopropanol, t-butyl alcohol,cyclohexanol, glycerin, glycerol, α-tocopherol (vitamin E) vegetableoil, sesame oil, soybean oil, cottonseed oil or peanut oil. The lipid,e.g., DOPC, was soluble over a wide range of solvent-to-lipid ratios.Lauryl lactate (LL) and N-methylpyrrolidone (NMP) as solvents incombination with lipid were chosen for further study.

Lipids can be dissolved in various non-aqueous liquid solvents indifferent ratios to adjust the viscosity of the vehicle from zero poiseto 1,000,000 poise. The formulations can thin with increasing shear, aphenomena that can increase the ease with which the vehicles can beprocessed. Studies have shown that DOPC in lauryl lactate (LL) andN-methylpyrrolidone (NMP) at weight ratios of 1.5:1 and 3:1lipid-to-solvent, respectively, have a viscosity of approximately 42,000and 15,000 poise, respectively, at 37° C. and shear rates of rangingfrom 0.04-10 sec⁻¹. These compositions have been shown to be shearthinning.

1,2-Dioleoyl-sn-glycero-3-phosphatidylcholine (DOPC) has a molecularweight of 786.13 kdalton, and a phase transition temperature of −18° C.

The high viscosity and shear thinning properties of lipid/solventsolutions suggest that they can be suitable vehicles for DUROS® implantsor OROS® osmotic delivery systems. See, for example, U.S. Pat. Nos.6,132,420; 6,174,547; 6,419,952; 6,551,613, each incorporated herein byreference in their entirety. The study has determined that ω-interferonin DOPC/solvent compositions, e.g., DOPC/lauryl lactate orDOPC/α-tocopherol, at 40° C. is stable for at least four weeks. TheDOPC/solvent compositions can be stable up to 3 months. A dissolutionand release rate study has determined that the lipid gels allow thedelivery of soluble ω-interferon into an aqueous environment.

“Amphiphilic molecule” refers to a molecule with distinct polar(hydrophilic) and non polar (hydrophobic) regions in the molecule. A“lipid” refers to a heterogeneous group of biological compounds that cancontain a large organic cation or anion which possesses a longunbranched hydrocarbon chain, e.g., H₃C(CH₂)_(n)CO₂ ⁻M⁺, H₃C(CH₂)_(n)SO₃⁻M⁺, H₃C(CH₂)_(n)N(CH₃)₃ ⁺X⁻ (n>7). The existence of distinct polar(hydrophilic) and non polar (hydrophobic) regions in the molecule canpromote the formation of micelles in dilute aqueous solution. “Cationiclipids” have a net positive charge. “Anionic lipids” have a net negativecharge. “Neutral lipids” have a net neutral charge.

“Lipid” refers to a heterogeneous group of biological compounds whichare sparingly soluble in water, but very soluble in nonpolar solvents.As a class, lipids can be defined by their solubility. They includechemically diverse compounds. “Natural lipids” include, but are notlimited to, triacylglycerols, waxes, and terpenes (e.g., monoterpenes,diterpenes, carotenoids or steroids). The more complex lipids includeglycolipids and phospholids. Triacylglycerols and waxes are known assaponifiable lipid, whereas terpenes are called nonsaponifiable lipid.“Saturated lipids” have all single bonded C—C hydrocarbon chains.“Unsaturated lipids” have one or more doubled bonded (C═C) or triplebonded (C≡C) hydrocarbon chains.

“Amphiphilic block polymer” refers to block copolymers such as Pluronic®block copolymer surfactants, (BASF Corporation, Mount Olive, N.J.; e.g.,Pluronic® surfactants or Pluronic® surfactant F-127), or sorbitan estersstructurants (e.g., Span® 80, Sigma Aldrich Chemical Co.) can be used,which can function as antifoaming agents, wetting agents, dispersants,thickeners, and emulsifiers. Pluronic® block copolymer surfactants canbe based on ethylene oxide and propylene oxide.

“Amphiphilic protein or peptide” refers to a polypeptide chain withdistinct polar (hydrophilic) and non polar (hydrophobic) regions in theprotein. The tertiary structure of protein is hydrophilic or highlycharged (positively or negatively charged) at one region of the protein,and is hydrophobic (non-polar) at another region of the protein.

Amphiphilic molecules useful in the present invention include, but arenot limited to, lipid, surfactant, amphiphilic block polymer, oramphiphilic proteins or peptides. Examples of amphiphilic molecules thatcan be suitable substances for forming a viscous liquid composition arefatty acid esters, e.g., glyceryl monoesters of fatty acids. Othersubstances which have ability of forming a viscous liquid compositioncan be found among amphiphilic substances such as polar lipids,surfactants and emulsifiers. Examples of glyceryl monoesters of fattyacids include glycerylmonooleate (monoolein) and glycerylmonolinoleate.

The “viscosity” of a fluid refers to resistance of the fluid to shear orflow, and is a measure of the fluid's adhesive/cohesive or frictionalproperties. This arises because of the internal molecular frictionwithin the fluid producing the frictional drag effect. Viscosity isuseful in the study of biopolymers because the addition of largemolecules to a solvent increases its viscosity; the increase depends onthe concentration, size, and structure of the polymer. Motion in onelayer of a fluid causes motion in adjoining layers. To move layers withdifferent relative velocities requires a force: the more viscous, themore force. Dynamic viscosity is also termed “absolute viscosity” and isthe tangential force per unit area required to move one horizontal planewith respect to the other at unit velocity when maintained a unitdistance apart by the fluid. The theoretical unit of viscosity is thePoise.

Fatty acid esters capable of forming a viscous liquid compositioncomprise a fatty acid component and a hydroxy-containing componentwherein the fatty acid component of the fatty acid ester is a saturatedor unsaturated fatty acid having a total number of carbon atoms of fromC₆ to C₂₆. Specific examples of saturated fatty acid moieties in thefatty acid esters according to the invention include, but are notlimited to, moieties of caproic acid, caprylic acid, capric acid, lauricacid, myristic acid, palmitic acid, stearic acid, arachidic acid, andbehenic acid. Specific examples of unsaturated fatty acid moieties inthe fatty acid esters according to the invention include, but are notlimited to, moieties of palmitoleic acid, oleic acid, linoleic acid,linolenic acid, and arachidonic acid. Further embodiments of fatty acidesters for use in compositions according to the invention include, butare not limited to, fatty acid esters of polyhydric alcohols, fatty acidesters of hydroxycarboxylic acids, fatty acid esters of monosaccharides,fatty acid esters of glycerylphosphate derivatives, fatty acid esters ofglycerylsulfate derivatives, and mixtures thereof. In those cases wherethe hydroxy-containing component of the fatty acid ester is polyvalent,the hydroxy-containing component can be partially or totally esterifiedwith a fatty acid component or with mixtures of fatty acid components.

The polyhydric alcohol component of the fatty acid ester for use incompositions according to the invention is preferably selected from thegroup consisting of glycerol, 1,2-propanediol, 1,3-propanediol,diacylgalactosyldycerol, diacyldigalactosylglycerol, erythritol,xylitol, adonitol, arabitol, mannitol, and sorbitol. The fatty acidesters formed from such polyhydric alcohols can be mono- or polyvalentsuch as, e.g., divalent, trivalent, etc. In particular fatty acidmonoesters have proved to have bioadhesive properties and can be fattyacid esters for use in compositions according to the invention. Theposition of the polyvalent alcohol on which the ester bond(s) is(are)established can be any possible position. In those cases where the fattyacid ester is a diester, triester, etc. the fatty acid components of thefatty acid ester can be the same or different. In a detailed aspect ofthe present invention, the polyhydric alcohol component can be glycerol.

Further examples of fatty acid esters for use in compositions accordingto the invention and wherein the hydroxy-containing component is apolyhydric alcohol include, but are not limited to, glycerylmonooleate,glycerylmonolinoleate, glycerol monolinoleate, and mixtures thereof.These fatty acid esters have bioadhesive properties useful in theviscous liquid compositions described herein. In those cases where thefatty acid ester for use in compositions according to the presentinvention is formed between a hydroxycarboxylic acid (or a derivativethereof) and a fatty acid (or a derivative thereof), thehydroxycarboxylic acid component of the fatty acid ester is preferablyselected from the group consisting of malic acid, tartaric acid, citricacid, lactic acid, and sorbic acid. An example of a fatty acid ester foruse in compositions according to the invention is a fatty acid monoesterof citric acid.

The hydroxy-containing component of a fatty acid ester for use incompositions according to the present invention can also be asaccharide, such as a monosaccharide such as, e.g., glucose, mannose,fructose, threose, gulose, arabinose, ribose, erythrose, lyxose,galactose, sorbose, altrose, tallose, idose, rhamnose, or allose. Inthose cases where the hydroxy-containing component is a monosaccharide,the fatty acid ester is preferably a fatty acid monoester of amonosaccharide selected from the group consisting of sorbose, galactose,ribose, and rhamnose. The hydroxy-containing component of a fatty acidester for use in the viscous liquid compositions can also be aglycerylphosphate derivative such as, e.g., a phospholipid selectedfrom, phosphatidylcholine (PC), phosphatidylethanolamine (PE),phosphatidylglycerol (PG), phosphatidylinositol (PI), phosphatidylserine(PS), phosphatidic acid (PA), or sphingomyelin (SM). ordiphosphatidylglycerol. Phospholipids can further include DEPE (1,2dielaidoyl-sn-glycerol-3-phosphoethanolamine) and DMPE (PEG 550)(1,2-dimyristoyl-sn-glycero-3-phosphoetiianolainine-N-(polyethyleneglycol)550).

Compounds having a phospholipid moiety further include compounds whereinthe fatty acid ester is a fatty acid ester of a glycerylphosphatederivative, and the fatty acid component is selected from the groupconsisting of lauric acid, myristic acid, palmitic acid, stearic acid,oleic acid, linoleic acid, linolenic acid, and behenic acid. Examples ofsuch useful fatty acid esters can be dilauryl phosphatidylcholine,dioleoyl phosphatidylcholine (DOPC), dimyritoylphosphatidylcholine(DMPC), dipalmitoylphosphatidylcholine (DPPC),distearoylphosphatidylcholine (DSPC), egg phosphatidylcholine (egg PC),soy phosphatidylcholine (soy PC), partially or fully hydrogenatedphosphatidylcholins (PHSPC or HSPC), palmitoyl-oleoylphosphatidylcholine (POPC), stearyloleoylphosphatidylcholin (SOPC),dibehenoyl phosphatidylcholine, dimyristyl phosphatidylethanolamine,dipalmitoyl phosphatidylethanolamine, dioleoyl phosphatidylglycerol(DOPG), dimyristoylphosphatidylglycerol (DMPG),dipalmitoylphosphatidylglycerol (DPPG), ordistearoylphosphatidylglycerol (DSPG), dilauryl phosphatidylglycerol,dipalmitoyl phosphatic acid and mixtures thereof.

Compounds that can be useful as amphiphilic molecules include, but arenot limited polyethyleneglycol (PEG)-lipid compound selected frommPEG-DPPE, mPEG-DMPE, mPEG-DSPE, or mPEG-ceramide-DSPE, and Pluronic®block copolymer surfactants, selected from PLURONIC® 17R2 surfactant,PLURONIC® 17R4 surfactant, PLURONIC® 25R2 surfactant, PLURONIC® 25R4surfactant, PLURONIC® 31R1 surfactant, PLURONIC® F108 cast solidsurfactant, PLURONIC® F108 NF cast solid surfactant, PLURONIC® F108 NFprill surfactant, PLURONIC® F108 pastille surfactant, PLURONIC® F108surfactant prill, PLURONIC® F127 cast solid surfactant, PLURONIC® F127NF 500BHT surfactant prill, PLURONIC® F127 NF cast solid surfactant,PLURONIC® F127 NF prill surfactant, PLURONIC® F127 surfactant prill,PLURONIC® F127NF 500BHT cast solid surfactant, PLURONIC® F38 cast solidsurfactant, PLURONIC® F38 surfactant pastille, PLURONIC® F68 LF pastillesurfactant, PLURONIC® F68 LF cast solid surfactant, PLURONIC® F68 NFcast solid surfactant, PLURONIC® F68 NF prill surfactant, PLURONIC® F68prill surfactant, PLURONIC® F68 surfactant, PLURONIC® F68 surfactantpastille, PLURONIC® F77 cast solid surfactant, PLURONIC® F77MICRO-pastille surfactant, PLURONIC® F87 cast solid surfactant,PLURONIC® F87 NF cast solid surfactant, PLURONIC® F87 NF prillsurfactant, PLURONIC® F87 prill surfactant, PLURONIC® F88 cast solidsurfactant, PLURONIC® F88 prill surfactant, PLURONIC® F88 surfactantpastille, PLURONIC® F98 cast solid surfactant, PLURONIC® F98 prillsurfactant, PLURONIC® L10 surfactant, PLURONIC® L101 surfactant,PLURONIC® L121 surfactant, PLURONIC® L31 surfactant, PLURONIC® L35surfactant, PLURONIC® L43 surfactant, PLURONIC® L44 NF surfactant,PLURONIC® L44 surfactant, PLURONIC® L61 surfactant, PLURONIC® L62 LFsurfactant, PLURONIC® L62 surfactant, PLURONIC® L62D surfactant,PLURONIC® L64 surfactant, PLURONIC® L81 surfactant, PLURONIC® L92surfactant, PLURONIC® N-3 surfactant, PLURONIC® P103 surfactant,PLURONIC® P104 surfactant, PLURONIC® P105 surfactant, PLURONIC® P123surfactant, PLURONIC® P65 surfactant, PLURONIC® P84 surfactant,PLURONIC® P85 surfactant, PLURONIC® F 127 micro pastille.

Compounds that can be useful as non-aqueous liquid solvent include, butare not limited to, lauryl lactate (LL), lauryl alcohol (LA), benzylalcohol (BA), benzyl benzoate (BB), 1:1 benzyl benzoate: benzyl alcohol,benzyl alcohol, ethyl hexyl lactate, glycerol formal, tetraglycol(glycofurol; GF), N-1-methyl-2-pyrrolidone (NMP), dimethyl sulfoxide,(DMSO), polyethyleneglycol (e.g., PEG 400), triglycerides (triolein,trilaurin, tricarprin, tricaprylin), ethanol, isopropanol, t-butylalcohol, cyclohexanol, glycerin, glycerol, α-tocopherol (vitamin E)vegetable oil, sesame oil, soybean oil, cottonseed oil or peanut oil.

Block copolymer surfactants (BASF Corporation, Mount Olive, N.J.; e.g.,Pluronic® surfactants or Pluronic® surfactant F-127), or sorbitan estersstructurants (e.g., Span®80, Sigma Aldrich Chemical Co.) can function asantifoaming agents, wetting agents, dispersants, thickeners, andemulsifiers. The Pluronic® type can be block copolymers based onethylene oxide and propylene oxide.

Most of the fatty acid esters for use in compositions according to theinvention can be chemical compounds which are commercially available orcan be prepared by means of esterification procedures involving e.g.,reaction of a fatty acid derivative such as, e.g., the correspondingacid chloride with a hydroxy-containing compound (if necessary protectedwith suitable protection groups) and subsequently isolating the fattyacid ester, if necessary after removal of any protecting group. Many ofthe commercially available fatty acid esters can be employed in the foodindustry and in general, no steps are taken in order to obtain anapproximately 100% pure fatty acid ester. For example,glycerylmonooleate (Danisco Ingredients A/S, Denmark) is a very pureproduct containing about 98% w/w monoesters of which more than about 80%w/w (such as about 92% w/w) is glycerylmonooleate. The remainingmonoesters can be glycerylmonolinoleate, glyceryl monopalmitate andglyceryl monostearate. The fatty acid ester products for use incompositions according to the invention can thus be mixtures of fattyacid esters. Examples of fatty acid esters with bioadhesive propertiesas well as an excellent ability of forming a viscous liquid compositioncan be glyceryl monoesters of fatty acids. Specific examples includeglycerylmonooleate (monoolein) and glycerylmonolinoleate.

The stability of the viscous liquid composition comprising anamphiphilic molecule and solvent is considerably enhanced, such asresulting in a storage stability of at least 2 years at 25° C., and atleast 1 month at 40° C. The fatty acid ester product fulfills certainpurity standards. Thus, the fatty acid ester product used for thepreparation of the composition should contain at the most 4% ofsaturated fatty acid ester and should preferably contain at least 88% offatty acid ester, more preferably at least 89%, such as at least 90% orat least 91%, in particular at least 92%, of fatty acid ester.

The amphiphilic molecule, e.g., lipid, is normally present in an amountof at least about 1% to about 100% by weight, calculated on the totalcomposition, such as at least 25% or at least 50%, or at least 75%, orat least 100% by weight, calculated on the total composition, and apreferred amount is often in the range of 25-90% such as 40-90% byweight, in particular, 40-85%, 45-80% or 50-75% by weight, calculated onthe total composition.

Normally, the concentration of the non-aqueous liquid solvent in acomposition according to the invention is about 0% to about 99% byweight, at least about 10% by weight such as, e.g., at least 20%, 30%,40%, 50%, 60%, or 70% by weight, or up to 99% by weight calculated onthe composition.

In other terms, the concentration of the non-aqueous liquid solvent inthe composition is in a range corresponding to from about 0% to about99% such as, e.g., about 15%-85%, about 20%-80%, about 25%-75%, about25%-70%, about 25%-65%, about 25%-60%, about 25%-55%, or about 25%-50%by weight based on the total composition.

Formation of the viscous liquid composition, in addition to comprisingan amphiphilic molecule, a non-aqueous solvent, and a pharmaceuticallyactive agent, can further comprise an amphiphilic substance having amolecular weight of, at most, 2000 daltons, or an emulsifier or asurfactant. Tenside surfactants (anionic, cationic, non-ionic like e.g.,sorbitan esters, sorbitan macrogol esters (polysorbates)), polar lipids,glycolipids, lecithins, palmitoyl muramic acid (PMA), substances havingsurface active properties like e.g., certain cellulose derivatives,sorbitan oleate, sorbitan laurate, lanolin and derivatives thereof andethoxylated derivatives of lanolin (Aqualose W20, Aqualose L30 andAqualose L75) are also examples of suitable structurants for use incompositions according to the invention. Sorbitan esters can be a seriesof mixtures of partial esters of sorbitol and its mono- anddi-anhydrides with fatty acids.

Examples of suitable sorbitan esters for use as structurants in acomposition according to the invention can be: sorbitan di-isostearate,sorbitan dioleate, sorbitan monoisostearate, sorbitan monolaurate,sorbitan monooleate (e.g., Span® 80, Sigma Aldrich Chemical Co.),sorbitan monopalmitate, sorbitan monostearate, sorbitansesqui-isostearate, sorbitan sesquioleate (e.g., Span® 83), sorbitantrioleate, sorbitan sesquistearate, sorbitan tri-isostearate, sorbitantristearate, sorbitan tristearate.

Polyoxyethylene sorbitan fatty acid esters (polysorbates) can be aseries of fatty acid esters or sorbitol and its anhydrides copolymerizedwith approximately 20 moles of ethylene oxide for each mole of sorbitoland its anhydrides. Examples of suitable polysorbates for use in thepresent context can be: polysorbate 20, polysorbate 21, polysorbate 40,polysorbate 60, polysorbate 61, polysorbate 65, polysorbate 80,polysorbate 81, polysorbate 85, polysorbate 120

In a further embodiment, suitable amphiphilic molecules for use in aviscous liquid composition include tocopherols. “Tocopherols” refers toall vitamin E or vitamin E-like substances, derivatives and analogsthereof. The term includes all tocol and tocotrienol derivatives such ase.g., methyl tocol. More specifically, in the present context, atocopherol is selected from the group consisting of p-tocopherols,sorbitan esters of tocopherols, d-α-tocopherol, d,l-α-tocopherol,d-α-tocopherol acetate, d,l-α-tocopherol acetate, d-α-tocopherolsuccinate, d,l-α-tocopherol succinate, d-α-tocopherol nicotinate,d,l-α-tocopherol nicotinate, tocopherylpolyethylene glycol succinatesuch as d-α-tocopherylpolyethylene glycol succinate ord,l-α-tocopherylpolyethylene glycol succinate, and derivatives such asfatty acid ester derivatives and analogues thereof. Tocopherols for usein a composition according to the present invention can be d-a-30. In afurther detailed embodiment, tocopherylpolyethylene glycol 1000succinate (in the following denoted vitamin E TPGS or simply TPGS) ord,l-α-tocopherylpolyethylene glycol 1000 succinate can be suitableamphiphilic molecules.

Fatty acid esters can be capable of forming various crystalline phasesupon contact with a hydrophilic medium such as water or glycerol. Thefatty acid esters also show bioadhesive properties. Viscous liquidcomposition can be a cubic (three cubic liquid crystalline phases arewell-characterized: i) the body-centered lattice, ii) the primitivediamond lattice, and iii) the gyroid), reverse cubic, hexagonal, reversehexagonal, lamellar, micellar or reverse micellar phase. By the term“cubic liquid crystalline phase” herein is meant a thermodynamicallystable, viscous and optically isotropic phase made of a suitablesubstance such as, e.g., a fatty acid ester and a liquid medium such as,e.g., a viscous liquid medium or an aqueous medium. The cubic liquidcrystalline phase is contemplated to be build up of closed reversedmicelles. The term “viscous liquid medium” includes media comprising anamphiphilic molecule and a non-aqueous liquid solvent. The term “aqueousmedium” includes media containing water or another hydrophilic andwater-miscible substance such as, e.g., glycerol. The terms “hexagonalphase” and “reverse hexagonal phase”, respectively, are used herein todescribe thermodynamically stable, viscous and optically anisotropicphases characterized by long-range order in two dimensions and made of asuitable substance such as, e.g., a fatty acid ester and a liquid mediumsuch as, e.g., a viscous liquid medium or an aqueous medium. The term“lamellar phase” is characterised by a long-range order in onedimension. The lamellar structure is the origin of liposomes havingspherical shells of lipid bilayers. The various liquid crystallinephases can be detected and identified by use of polarized light or bymeans of X-ray diffraction pattern analysis. The cubic liquidcrystalline phase is normally the preferred phase in the compositions ofthe invention, but also, e.g., the reverse hexagonal and the reversecubic liquid crystalline phase can be a liquid crystalline phase in thecompositions according to the invention.

Pharmaceutically Active Agents

“Pharmaceutically active agent” refers to any biologically orpharmacologically active substance or antigen-comprising material; theterm includes drug substances which have utility in the treatment orprevention of diseases or disorders affecting animals or humans, or inthe regulation of any animal or human physiological condition and italso includes any biologically active compound or composition which,when administered in an effective amount, has an effect on living cellsor organisms. The pharmaceutically active agent includes, but is notlimited to a protein, peptide, small molecule drug, lipid drug ornucleic acid drug (e.g., DNA, RNA, antisense, ribozyme, DNAzyme.

Examples of active substances of particular importance with respect toall aspects of the invention can be the so-called antiherpes virusagents which have been or are developed for the treatment of herpesvirus infections [herpes simplex virus types 1 and 2 (HSV-1 and HSV-2),varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus(EBV)]. The antiherpes virus agents include antiviral drugs and prodrugsthereof, such as nucleosides, nucleoside analogues, phosphorylatednucleosides (nucleotides), nucleotide analogues and salts, complexes andprodrugs thereof; e.g., guanosine analogues, deoxyguanosine analogues,guanine, guanine analogues, thymidine analogues, uracil analogues andadenine analogues. Antiherpes virus agent for use either alone or incombination in a composition according to the present invention can beselected from acyclovir, famciclovir, deciclovir, penciclovir,zidovudin, ganciclovir, didanosin, zalcitabin, valaciclovir, sorivudine,lobucavir, brivudine, cidofovir, n-docosanol, ISIS-2922, and prodrugsand analogues thereof. Details concerning active substances suitable foruse in connection with the present invention as well as a description ofother active substances are given below.

As mentioned above, an important example of an active substance is anantiviral drug, such as a nucleoside or a nucleoside analogue, e.g.,selected from acyclovir, famciclovir, deciclovir, penciclovir,zidovudin, ganciclovir, didanosin, zalcitabin, valaciclovir, sorivudine,lobucavir, brivudine, cidofovir, n-docosanol, ISIS-2922 and salts andprodrugs thereof. However, also a large number of other drugs which inthemselves have a low solubility as denned herein or the salts, esters,prodrugs or precursors of which have a low solubility can be importantactive substances in the compositions of the invention. Furthermore,there is also a large number of drugs which advantageously can beincorporated in a composition according to the invention, either as thesole active substance (provided the solubility criteria can befulfilled) or in combination with another active substances. In thefollowing is listed a number of active substances which either alone orin combination can be incorporated in a composition according to thepresent invention. In particular a combination of an anti-herpes virusagent and a glucocorticosteroid is of importance.

Examples of drugs which can be of particular importance in connectionwith application to skin or mucosal surfaces are: Acyclovir,famciclovir, ribavirin, zidovudin, ganciclovir, didanosin, zalcitabin,valaciclovir amantadin, rimantadin foskarnet idoxuridin fluoruracilinterferons and variants thereof, including α-interferon, β-interferon,γ-interferon, ω-interferon, tromantadin, lentinan, levofloxacin,stavudine, tacrine, vesnarinone, ampligen, atevirdine, delavirdine,hydroxyurea, indinavir sulfate, interleukin-2 fusion toxin, seragen,lamivudine, lidakol, nevirapine, onconase, saquinavir, topotecan,verteporfin, viraplex, CMV immunoglobulin, Efalith, epervudine,podophyllotoxin, proxigermanium, rifabutin, bromovinyldeoxyuridine,ukrain, cidofovir, imiquimod, lamivudine, sorivudine, viraplex afovirsenamonafide hypericin, provir, temoporfin, apbidicolin glycinate,ibobucavir, virend, AL-721, ampligen, arildone, brivudine,CD4,2-deoxy-D-glucose, desciclovir, dichloroflavan, didanosine,ditiocarb Sodium edoxudine, enviroxime, fiacitabine, inosine Pranobex,peptide T stavudine tribavirin trifluridine vidarabine zalcitabine,miconazol fucidin, erythromycin macrolides, NSAID's, peptides insulin,polymycin, myperizin, antibiotics, nicotine sucralfate, sucroseoctasulfate, salicylic acid, urea, benzoylperoxide minoxidil,heparinoid, methotrexate, ciclosporin.

A listing of substances of potential interest comprises substances ofthe following groups: sodium fluoride, anti-inflammatory drugs such as,e.g., ibuprofen, indomethacin, naproxen, diclofenac, tolfenamic acid,piroxicam, and the like; narcotic antagonists such as, e.g., naloxone,nalorphine, and the like; antiparkinsonism agents such as, e.g.,bromocriptine, piperidin, benzhexyl, benztropine, and the like;antidepressants such as, e.g., imipramine, nortriptyline, pritiptylene,and the like; antibiotic agents such as, e.g., clindamycin,erythromycin, fusidic acid, gentamicin, mupirocien, amfomycin, neomycin,metronidazole, silver sulphadiazine, sulphamethizole, bacitracin,framycetin, polymycin B, acitromycin, and the like; antifungal agentssuch as, e.g., miconazol, ketoconazole, clotrimazole, amphotericin B,nystatin, mepyramin, econazol, fluconazol, flucytocine, griseoftdvin,bifonazole, amorolfine, mycostatin, itraconazole, terbenafine,terconazole, tolnaftate, and the like; antimicrobial agents such as,e.g., metronidazole, tetracyclines, oxytetracycline, and the like;antiemetics such as, e.g., metoclopramide, droperidol, haloperidol,promethazine, and the like; antihistamines such as, e.g.,chlorpheniramine, terfenadine, triprolidine, and the like; antimigraineagents such as, e.g., dihydroergotamine, ergotamine, pizotyhne, and thelike; coronary, cerebral or peripheral vasodilators such as, e.g.,nifedipine, diltiazem, and the like; antianginals such as, e.g.,glyceryl nitrate, isosorbide denitrate, molsidomine, verapamil, and thelike; calcium channel blockers such as, e.g., verapamil, nifedipine,diltiazem, nicardipine, and the like; hormonal agents such as, e.g.,estradiol, estron, estriol, polyestradiol, polyestriol, dienestrol,diethylstilbestrol, progesterone, dihydroergosterone, cyproterone,danazol, testosterone, and the like; contraceptive agents such as, e.g.,ethynyl estradiol, lynestrenol, etynodiol, norethisterone, mestranol,norgestrel, levonorgestrel, desogestrel, medroxyprogesterone, and thelike; antithrombotic agents such as, e.g., heparin, warfarin, and thelike; diuretics such as, e.g., hydrochlorothiazide, flunarizine,minoxidil, and the like; antihypertensive agents such as, e.g.,propanolol, metoprolol, clonidine, pindolol, and the like;corticosteroids such as, e.g., beclomethasone, betamethasone,betamethasone-17-valerate, betamethasone-dipropionate, clobetasol,clobetasol-17-butyrate, clobetasol-propionate, desonide,desoxymethasone, dexamethasone, diflucortolone, flumethasone,flumethasone-pivalate, fluocinolone acetonide, fluocinonide,hydrocortisone, hydrocortisone-17-butyrate, hydrocortisone-buteprate,methylprednisolone, triamcinolone acetonide, budesonide, halcinonide,fluprednide acetate, alklometasone-dipropionate, fluocortolone,fluticason-propionate, mometasone-furate, desoxymethasone,diflurason-diacetate; halquinol, cliochinol, chlorchinaldol,fluocinolone-acetonid, and the like; dermatological agents such as,e.g., nitrofurantoin, dithranol, clioquinol, hydroxyquinoline,isotretionin, methoxsalen, methotrexate, tretionin, trioxsalen,salicylic acid, penicillamine, and the like; steroids such as, e.g.,estradiol, progesterone, norethindrone, levonorgestrol, ethynodiol,levenorgestrel, norgestimate, gestanin, desogestrel,3-keton-desogestrel, demegestone, promethoestrol, testosterone,spironolactone, and esters thereof, nitro compounds such as, e.g., amylnitrates, nitroglycerine and isosorbide nitrates, opioid compounds suchas, e.g., morphine and morphine-like drugs such as buprenorphine,oxymorphone, hydromorphone, levorphanol, fentanyl and fentanylderivatives and analogues, prostaglandins such as, e.g., a member of thePGA, PGB, PGE, or PGF series such as, e.g., misoprostol, dinoproston,carboprost or enaprostil, a benzamide such as, e.g., metoclopramide,scopolamine, a peptide such as, e.g., growth hormone releasing factors,growth factors (epidermal growth factor (EGF), nerve growth factor(NGF), TGF, PDGF, insulin growth factor (IGF), fibroblast growth factor(FGFα, FGFβ, etc.), and the like), somatostatin, calcitonin, insulin,vasopressin, interferons, interleukins, e.g., IL-2, IL-12, IL-21,urokinase, serratiopeptidase, superoxide dismutase (SOD), thyrotropinreleasing hormone (TRH), luteinizing hormone releasing hormone (LH-RH),corticotrophin releasing hormone (CRF), growth hormone releasing hormone(GHRH), oxytocin, erythropoietin (EPO), colony stimulating factor (CSF),and the like, a xanthine such as, e.g., caffeine, theophylline, acatecholamine such as, e.g., ephedrine, salbutamol, terbutaline, adihydropyridine such as, e.g., nifedipine, a thiazide such as, e.g.,hydrochlorotiazide, flunarizine, others such as, e.g., propanthelin,silver nitrate, enzymes like Streptokinases, Streptodases, vitamins likevitamin A, tretionin, isotretionin, acitretin, vitamin D, calcipotriol,interferon-α-2b, selen disulfide, pyrethione. It will be understood thatthe compositions of the invention can also comprise combinations ofactive substances, e.g., an active substance together with a potentiatortherefor. It will of course also be understood that in the aspects ofthe invention wherein there is no specific requirement to the activesubstance, e.g., with respect to solubility, any substance which has atherapeutic or prophylactic activity can be incorporated in thecomposition.

Pharmaceutically Acceptable Excipients for Use in a Viscous LiquidComposition

An aspect of the invention relates to compositions wherein at least apart of the viscous liquid composition at room temperature can besubstituted by certain pharmaceutically acceptable excipients. Additionof a pharmaceutically acceptable excipient to a viscous liquidcomposition or a precursor composition will normally lead to adisruption in the viscous liquid composition. Therefore, such substanceis generally only added in very small concentrations such as, e.g.,about 1-5% by weight based on the total composition. Certainpharmaceutically acceptable excipients can be added in much largerconcentrations without having any substantially negative influence onthe biopharmaceutical properties of the composition. Thus, theconcentration of such excipients can be at least about 5% by weight suchas, e.g., at least about 8%, 9%, 10%, 15% or 20% by weight.

Examples of suitable pharmaceutically acceptable excipients can be founde.g., among inert diluents or fillers selected from the group consistingof sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose,carboxymethylcellulose sodium, methylcellulose, hydroxypropylmethylcellulose, ethylcellulose, starches including potato starch,calcium carbonate, sodium chloride, lactose, calcium phosphate, calciumsulfate, sodium phosphate, and a polysaccharide such as, e.g.,carmelose, a chitosan, a pectin, xanthan gum, a carrageenan, locust beangum, acacia gum, a gelatin, an alginate, and dextrans and salts thereof.

Examples of suitable pharmaceutically excipients which can be soluble inthe second substance or in the liquid crystalline phase are e.g.,sorbitan esters such as, e.g., polysorbates; and macrogols. In thepresent context, solvents like e.g., water, glycerol, alcohols likee.g., ethanol and isopropylalcohol are examples of a liquid medium andare not intended to be examples of soluble pharmaceutically acceptableexcipients.

Pharmaceutical Compositions and Routes of Administration

The viscous liquid composition in an osmotic delivery system is intendedfor parenteral administration and for topical administration to skin ormucosa. Other applications can of course also be relevant such as, e.g.,application on dentures, prostheses and application to body cavitiessuch as the oral cavity. The mucosa is preferably selected from oral,nasal, aural, lung, rectal, vaginal, and gastrointestinal mucosa.

A bioadhesive composition for administration according to the inventioncan also be in the form of a multiple unit composition, in the form of,e.g., a powder. A multiple unit composition can be administered to skinor mucosa, preferably the mucosa is selected from oral, nasal, rectal,aural, vaginal, lung, and gastrointestinal mucosa. Most preferred is abioadhesive composition intended for administration to thegastrointestinal tract.

Bioadhesive compositions according to the invention for application onskin can comprise a polysaccharide in a concentration of at least 15%w/w, calculated on the total weight of the composition. Thepolysaccharide is preferably selected from the group consisting ofcarmelose, chitosan, pectins, xanthan gums, carrageenans, locust beangum, acacia gum, gelatins, alginates, and dextrans, and salts thereof.The compositions can be easy to apply on the wound and are believed tobe able to extract water from the wound and thereby drying the wound.Apart from the active or protective substance and the bioadhesive fattyacid ester substance, the bioadhesive compositions for use according tothe invention can comprise pharmaceutically or cosmetically acceptableexcipients or additives normally used in pharmaceutical compositions.

The bioadhesive compositions can be in form of, e.g., a spray, asolution, a dispersion, a suspension, an emulsion, powders, gelsincluding hydrogels, pastes, ointments, creams, drenches, deliverydevices, suppositories, enemas, implants, aerosols, microcapsules,microspheres, nanoparticles, liposomes, dressings, bandages, plasters,tooth paste, dental care compositions, and in other suitable form. Thebioadhesive compositions can be formulated according to conventionalpharmaceutical practice, see, e.g., “Remington's PharmaceuticalSciences” and “Encyclopedia of Pharmaceutical Technology”, edited bySwarbrick, J. & J. C. Boylan, Marcel Dekker, Inc., New York, 1988.Pharmaceutically acceptable excipients for use in bioadhesivecompositions for use according to the invention can be, for example,inert diluents or fillers, such as sucrose, sorbitol, sugar, mannitol,microcrystalline cellulose, carboxymethylcellulose sodium,methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, starchesincluding potato starch, calcium carbonate, sodium chloride, lactose,calcium phosphate, calcium sulfate or sodium phosphate; and lubricatingagents including glidants and antiadhesives, for example, magnesiumstearate, zinc stearate, stearic acid, silicas, hydrogenated vegetableoils or talc. Other pharmaceutically acceptable excipients can becolorants, flavouring agents, plasticizers, humectants, bufferingagents, solubilizing agents, release modulating agents, etc. Forapplication to the rectal or vaginal mucosa suitable compositions foruse according to the invention include suppositories (emulsion orsuspension type), suspensions, solutions, enemas, and rectal gelatincapsules (solutions or suspensions). Appropriate pharmaceuticallyacceptable suppository bases include cocoa butter, esterified fattyacids, glycerinated gelatin, and various water-soluble or dispersiblebases like polyethylene glycols and polyoxyethylene sorbitan fatty acidesters. Various additives like, e.g., enhancers or surfactants can beincorporated.

For application to the nasal mucosa, nasal sprays and aerosols forinhalation can be suitable compositions for use according to theinvention. In a typically nasal formulation, the active ingredients canbe dissolved or dispersed in a suitable vehicle. The pharmaceuticallyacceptable vehicles and excipients and optionally other pharmaceuticallyacceptable materials present in the composition such as diluents,enhancers, flavouring agents, preservatives etc. are all selected inaccordance with conventional pharmaceutical practice in a mannerunderstood by the persons skilled in the art of formulatingPharmaceuticals.

For application to the oral cavity, teeth, skin or nail, thecompositions for use according to the invention can containconventionally non-toxic pharmaceutically acceptable carriers andexcipients including microspheres and liposomes. The formulationsinclude creams, ointments, lotions, liniments, gels, hydrogels,suspensions, solutions sticks, sprays, pastes, dressings, bandages,plasters, tooth paste, dental care compositions, and the like. Thepharmaceutically acceptable carriers or excipients can includeemulsifying agents, stabilizing agents, antioxidants, buffering agents,preservatives, humectants, penetration enhancers, chelating agents, gelforming agents, ointment bases, perfumes and skin protective agents.

Examples of emulsifying agents can be naturally occurring gums, e.g.,gum acacia or gum tragacanth, naturally occurring phosphatides, e.g.,soybean lecithin and sorbitan monooleate derivatives. Examples ofantioxidants can be butylated hydroxy anisole (BHA), ascorbic acid andderivatives thereof, a-tocopherol and derivatives thereof, vitamin E,salts of sulphur dioxide, cysteine, citric acid, ascorbyl palmitate,butylhydroxytoluene, complexing agents, chelating agents, sodiumpyrosulfite, EDTA and gallic acid esters. Examples of preservatives canbe parabens, such as methyl, ethyl, propyl p-hydroxybenzoate,butylparaben, isobutylparaben, isopropylparaben, potassium sorbate,sorbic acid, benzoic acid, methyl benzoate, phenoxyethanol, bronopol,bronidox, MDM hydantoin, iodopropynyl butylcarbamate, EDTA,propyleneglycol (increases the solubility of preservatives) benzalconiumchloride, benzylalcohol, chlorhexidine diacetate, chlorhexidinedigluconate, chlorbntol, phenetanol, phenols (phenol, o-cresol,p-cresol, chlorcresol, tricresol), alkanols (chlorbutanol, phenetanol),sorbic acid, and mercuri-compounds like e.g., phenylmercurinitrate.Examples of humectants can be glycerin, propylene glycol, sorbitol andurea. Examples of suitable release modulating agents for use accordingto the invention can be glycerol, sesame oil, soybean oil, lecithin andcholesterol. Examples of penetration enhancers can be oleic acid,propylene glycol, DMSO, triethanolamine, N,N-dimethylacetamide_(r)N,N-dimethylformamide, 2-pyrrolidone and derivatives thereof,-tetrahydrofuryl alcohol and Azone. Examples of chelating agents can besodium EDTA, citric acid and phosphoric acid. Examples of otherexcipients for use in compositions for use according to the inventioncan be edible oils like almond oil, castor oil, cacao butter, coconutoil, corn oil, cottonseed oil, linseed oil, olive oil, palm oil, peanutoil, poppyseed oil, rapeseed oil, sesame oil, soybean oil, sunfloweroil, and teaseed oil; and of polymers such as carmelose, sodiumcarmelose, hydroxypropylmethylcellulose, hydroxyethylcellulose,hydroxypropylcellulose, chitosane, pectin, xanthan gum, carrageenan,locust bean gum, acacia gum, gelatin, and alginates, and solvents suchas, e.g., glycerol, ethanol, propylene glycol, polyethylene glycols suchas PEG 200 and PEG 400, Pluronic, polysorbate, and ethylene glycol.Examples of ointment bases can be beeswax, paraffin, cetyl palmitate,vegetable oils, sorbitan esters of fatty acids (Span®), Carbopol®,polyethylene glycols, and condensation products between sorbitan estersof fatty acids and ethylene oxide, e.g., polyoxyethylene sorbitanmonooleate (Tween®).

Pharmaceutically acceptable carriers can be determined in part by theparticular composition being administered, as well as by the particularmethod used to administer the composition. Accordingly, there is a widevariety of suitable formulations of pharmaceutical compositions foradministering a pharmaceutically active agent in a viscous liquidcomposition (see, e.g., Remington's Pharmaceutical Sciences, MackPublishing Co., Easton, Pa. 18^(th) ed., 1990, incorporated herein byreference). The pharmaceutical compositions are generally formulated assterile, substantially isotonic and in full compliance with all GoodManufacturing Practice (GMP) regulations of the U.S. Food and DrugAdministration.

Reference to “performance modifiers” means those materials that help toimprove the stability and/or performance of lipid-based suspendingvehicles. In some embodiments, such improvements include changing theproperties of a two-component vehicle, that is already a stable solutionof lipid in non-aqueous solvent, by altering the viscosity or otherproperties of a vehicle. Other aspects of the invention includeimproving the solubility of one component in the other, thus stabilizingthe vehicle.

Performance modifiers that reduce stiff phases that are sometimes formedon contact of a amphiphilic-based suspending vehicle with aqueous mediuminclude, but are not limited to, ethyl acetate, sesame oil, dioctylsulfosuccinate, cholesterol, polysorbate 20, polysorbate 80, sodiumdodecyl sulfate, fatty acids like oleic, stearic, linoleic, myristic,tocopheryl acetate, and vitamin E TPGS.

Performance modifiers that are cosolvents, that may act a dissolutionrate enhancer, phase modifier, viscosity modifier or processing aidinclude but are not limited to ethanol, tocopherols, vegetable oils(sesame, cottonseed, safflower, coconut, soybean, olive),caprylic/capric triglycerides, ethyl acetate, benzyl alcohol,glycofurol, theyl oleate, N, N dimethyl acetamide, polyoxaester liquidpolymers, N-methylpyrrolidone, polysorbate 80, polysorbate 20, castoroil, isopropyl myristate, triacetin, polyethylene glycol, lauryllactate, lauryl alcohol, and combinations thereof.

Performance modifiers in accordance with the present invention can beused, for example, to improve the stability and/or the flowability oflipid-based suspending vehicles. For example, the use of performancemodifiers aids in softening formations made at exit ports upon contactby the suspending vehicle with aqueous media, for example, bodilyfluids. Performance modifiers, such as co-solvents, can also speed-uppreparation of suspending vehicles and suspensions due to increasedsolubility of the lipid in co-solvents relative to a non-aqueoussolvent. Performance modifiers can also be useful for reducing viscosityvariations over small composition variations.

Reference to “suspending vehicle” means that the pharmaceutically activeagent is substantially insoluble therein. Materials that aresubstantially insoluble generally remain in their original physical formthroughout the lifespan of a dosage form containing the suspension. Forexample, solid particulates would generally remain particles. Ifnecessary, the suspending vehicle may have other materials dissolved inthem.

Reference to “stiff gels” means the gels that form within a suspendingvehicle or pharmaceutical suspension upon contact with an aqueous mediumthat may be pliable but are substantially hard enough that they wouldimpede flow out of a dosage form.

Furthermore, relevant compositions and conditions to be fulfilled forthe individual components in the compositions are claimed in the claimsand described in the Examples.

Example 1

An exemplary embodiment of liquid viscous compositions comprising atherapeutic protein or drug is the protein ω-interferon (ω-IFN) in aliquid composition of 1,2-Dioleoy-sn-glycero-3-phosphatidylcholine(DOPC): N-methylpyrrolidone (NMP) (3:1 w/w) or in a liquid compositionof DOPC: lauryl lactate (LL) (3:2 w/w). A summary of resultsdemonstrates that: (1) Protein release occurs from the liquid viscouscompositions into a sink of aqueous media; (2) Release rate of ω-IFNfrom a composition comprising lauryl lactate:DOPC vehicles demonstratesthat release occurs at a therapeutically effective rate to confirmfeasibility; (3) ω-IFN in anhydrous suspension is stable; (4)α-tocopherol in combination with DOPC or DMPC can further includecompounds to modify the rheological properties of the vehicle itself.

The objectives of the study are to: (a) assess the preliminary stabilityof ω-interferon at 40° C. in vehicles composed of a lipid(1,2-Dioleoy-sn-glycero-3-phosphatidylcholine (DOPC)) and a solvent(lauryl lactate (LL) or N-methylpyrrolidone (NMP)), (b) investigate therelease of w-interferon from these vehicles into aqueous media, and (c)evaluate pump performance using lipid-based vehicles in a release ratestudy.

1.1 Plan of Study

TABLE 1 Characterization of Various materials Material Test Method NMPPeroxide Content EP 2000 2.5.5 Method A or Oxis Method Vehicles MoistureContent Karl Fischer Protein Particles Protein Content RP-HPLC and SEC

Preparation and Evaluation of Suspension

Control particles (1:2:1 Protein:Sucrose:Methionine with 25 mM citratebuffer) was used for the study. The particle loading was approximately10%, which is equivalent to drug loading of 1.67%. This is consistentwith a unit dose of 25 μg/day.

The suspension is prepared in a dry box under nitrogen. Suspensioncomposition is presented in Table 2 and 3.

TABLE 2 Composition of DOPC/NMP Formulation DOPC/NMP Formulation IDPDP7-176-1, 3 Particle Source Spray-dried in Palo Alto facility VehicleLoading (3:1 DOPC:NMP) 90% Particle Loading 10% Protein Concentration1.67%  

TABLE 3 Composition of DOPC/LL Formulation DOPC/LL Formulation IDPDP7-176-2, 4 Particle Source Spray-dried in Palo Alto facility VehicleLoading (3:2 DOPC:LL) 90% Particle Loading 10% Protein Concentration1.67%  

Stability of the suspension was measured after storage at 40° C. undernitrogen in lyophilization vials. Stability samples was tested intriplicate at t=0, 2, and 4 weeks (5 mg ω-interferon per timepoint).Analysis was performed using RP-HPLC to determine purity with respect tooxidation and deamidation and using SEC to determine purity with respectto aggregation and precipitation.

A dissolution study was run with 6 mg formulation in 2 mL phosphatebuffered saline (PBS) in Vacutainers®. These samples was incubated at40° C. and tested at t=0, 1, 3, and 7 days.

Release rate formulations was prepared after results for t=0 stabilityand t=1 week dissolution samples are generated (assuming reasonableprotein recoveries).

TABLE 4 Tests and Observations to be made on the Dynamic Capillary TubeSamples in Exp. PDP7-176 Test to be Performed Frequency and Details ofTest X-Ray to determine Before immersing membrane in PBS buffer locationof piston and approximately every two weeks thereafter Quantify solubleand Samples were collected approximately twice insoluble ω-interferonper week. Quantify protein with HPLC or released from implant otheranalytical method. Guanidine HCl used to redissolve insoluble protein.Visual observations of Approximately weekly once glass tubes are glasscapillary tubes immersed in PBS. Visual measurement of Weekly once glasstubes are immersed in PBS. water ingress into glass capillary tubes

Suspension Preparation

Suspensions for stability and dissolution testing was prepared at atarget batch size of 2.0 grams. This batch size is determined by thequantity of protein particles required. Suspension is prepared in a drybox under nitrogen.

Lauryl Lactate/DOPC Vehicle and Suspension Preparation for Use inRelease Rate, Stability, and Dissolution Testing

-   -   1. Preheat a hot plate to maintain a target surface temperature        of 80° C.    -   2. Weigh 3.00 g DOPC    -   3. Weigh 2.00 g LL    -   4. Heat to 80° C. on hot plate and mix with stainless steel        spatula by hand    -   5. Transfer 2.025 g of Vehicle and add 0.225 g of protein        particles.    -   6. Using a stainless steel spatula, manually incorporate the        protein particles into the vehicle. Continue to hand mix the        suspension for 15 minutes while warming on the hot plate.    -   7. Fill suspension into syringe, de-aerate under vacuum, seal        syringe and store refrigerated.        NMP/DOPC Vehicle and Suspension Preparation for Use in Release        Rate Testing    -   1. Preheat a hot plate to maintain a target surface temperature        of 80° C.    -   2. Weigh 3.75 g DOPC    -   3. Weigh 1.25 g NMP    -   4. Heat to 80° C. on hot plate and mix with stainless steel        spatula by hand    -   5. Transfer 2.025 g of Vehicle and add 0.225 g of protein        particles.    -   6. Using a stainless steel spatula, manually incorporate the        protein particles into the vehicle. Continue to hand mix the        suspension for 15 minutes while warming on the hot plate.    -   7. Fill suspension into syringe, de-aerate under vacuum, seal        syringe and store refrigerated.

1.2 Particle Preparation

Protein-excipient solution was spray dried to result in spray-driedparticles. Particle size can be from about 1 to about 10 μm in diameter.Other procedures for creating particles include, but are not limited to,lyophilization or supercritical fluid processing.

1.3 System Assembly

Systems were assembled by loading suspension of the liquid compositioninto a formulation compartment of the osmotic delivery device. A capwith an orifice was slowly screwed onto the shell of the osmoticdelivery device. The exit orifice serves as a diffusion moderator forrelease of the liquid composition.

Example 2

Table 5 shows the solubility of a therapeutic protein, ω-interferon, inan non-aqueous liquid solvent. Thirteen non-aqueous liquid solventcandidates were identified to develop a solution formulation or asuspension formulation based on solubility of ω-interferon. The solventsat the top, e.g., lauryl lactate, are potential suspension solvents. Thecharacter of the solvents changes to potential solution solvents incombination with ω-interferon, e.g., glycerol formal, benzyl benzoate,DMSO, or glycerin.

Non-aqueous liquid solvents, such as glycerol formal, benzyl benzoate,DMSO, or glycerin are useful in combination with small moleculetherapeutic drugs, therapeutic lipid prodrug, or therapeutic protein toform suspension formulations with drugs. Furthermore, non-aqueous liquidsolvents, such as lauryl lactate, lauryl alcohol, NMP, ethanol, PEG 400,1:1 benzyl benzoate: benzyl alcohol, benzyl alcohol, ethyl hexyl lactateare useful in combination with small molecule therapeutic drugs,therapeutic lipid prodrug, or therapeutic protein to form suspensionformulations with drugs.

TABLE 5 ω-Interferon Solubility in Non-aqueous liquid solventsConcentration Concentration Concentration Expected Conc Solvent by UV(mg/ml) by rp-HPLC by SEC (mg/ml) (mg/ml) Lauryl lactate <0.1 N/A N/A10.00 Lauryl alcohol <0.1 N/A N/A 10.00 NMP <0.1 0.00 0.00 25.00 Ethanol<0.1 0.00 0.00 25.00 PEG 400 <0.1 0.00 0.00 25.00 1:1 Benzyl benzoate:<0.1 0.00 0.00 10.00 Benzyl alcohol Benzyl alcohol 0.14 0.00 0.00 10.00Ethyl hexyl lactate 0.37 0.00 0.00 10.00

Example 3

FIG. 1 shows the shear rate effect on various DOPC vehicle formulationsat 37° C. DOPC vehicle formulations that were tested include, DOPC/DMSO(3:1), DOPC/Gly (2.45:1), DOPC/NMP (2:1), DOPC/LL (2:1), DOPC/LA (2:1).The results demonstrate that at increasing shear rate DOPC formulationscan be shear thinning. Shear thinning is an important property tofacilitate the manufacturing process of the viscous liquid formulations.

Example 4

FIG. 2 shows the temperature effect on viscosity of DOPC formulations.The viscosity of various DOPC formulations was measured at varioustemperatures under a shear stress of 0.04 per second. The resultsindicate that viscosity of DOPC formulations is temperature dependent.

Example 5

FIG. 3 shows the shear rate effect on various PHSPC vehicle formulationsat 37° C. PHSPC vehicle formulations that were tested include PHSPC/GF(1:1), PHSPC/LL (1:1), PHSPC/LA (2:1), PHSPC/GF (2.5:1). The resultsdemonstrate that at increasing shear rate PHSPC formulations can beshear thinning. Shear thinning is an important property to facilitatethe manufacturing process of the viscous liquid formulations.

Example 6

FIG. 4 shows the temperature effect on viscosity of PHSPC formulations.The viscosity of various PHSPC formulations was measured at varioustemperatures under a shear stress of 0.04 per second. The resultsindicate that viscosity of PHSPC formulations is temperature dependent.

Example 7

FIG. 5 displays images of DOPC formulations, e.g., DOPC/NMP (3:1),DOPC/LL (1:1), DOPC:H₂O (1:9) visualized by polarized microscopy. Allsamples are birefringent, suggesting formation of lipid vesicles in thesuspension.

Example 8

FIG. 6 displays images of PHSPC formulations, e.g., PHSPC/GF (1:1),PHSPC/LL (1:1), PHSPC:H₂O (1:9), PHSPC/LA (2:1), as visualized bypolarized microscopy. PHSPC/LL formulation is not birefringentsuggesting dissolution of PHSPC in LL. However all other samples arebirefringent, suggesting formation of lipid vesicles in the suspension.

Example 9

Table 6 summarizes the solubility and rheology of lipids in varioussolvents. Parameters measured were viscosity at 37° C. (in poise), shearthinning at 37° C. (sec⁻¹), temperature effect on viscosity (poise).

TABLE 6 Rheology and Solubility of Lipids in Non-aqueous liquid solventsTemp Lipid:Solvent Viscosity at Shear Thinning effect Viscosity LipidSolvent Ratio 37° C. (poise) at 37° C. (1/s) (° C.) (poise) CommentsDOPC BA 1.35 1 Low viscosity to the eye DOPC BA 1.78 1 Low viscosity tothe eye DOPC NMP 2 1 33000-170   0.04-10 5-47 114000-1380  DOPC NMP 2.81 12900 0.04 5-70 12600-8200 No stress sweep data DOPC NMP 3.5 1 195000.04 5-70 200000-9000  No stress sweep data DOPC GF 0.5 1 Low viscosityto the eye DOPC GF 1 1 Low viscosity to the eye DOPC GF 2.45 1   10 NoNo DOPC DMSO 3 1 35000-700   0.04-2.5 5-70  5e4-5e3 DOPC LL 2 1  420000-7QOQO   0.04-0.25 5-70   2e6-4,5e4 DOPC LA 2 1 8760-870 0.04-110-35   3.7e5-4.8e4 Gel crash above 35° C. PHSPC GF 1 1 5220-440 0.04-15-70     5e3-9.5e−1 PHSPC GF 2.5 1 1300-700 0.04-1 10-70  2.25e4-2.8e2PHSPC LL 1 1 13000-130    0.04-0.65 5-70 2e4-3  PHSPC LA 2 1 125 No20-70  7e3-5 

Example 10

Table 7 summarizes moisture levels in lipid vehicles. The moisture levelof the lipid, e.g., DOPC, HSPC, PHSPC, or DMPC, is measured after vacuumat room temperature for 48 hours. Lipid vehicles with lower moisturelevel can be included in viscous liquid compositions.

TABLE 7 Lipid Moisture Level Lipid Avg. Moisture (%) DOPC 0.6 ± 0.2 HSPC1.85 ± 0.64 PHSPC 1.02 ± 0.52 DMPC 0.6

Example 11

FIG. 7 shows a shear rate effect on a DOPC:LL vehicle formulation at 37°C. The vehicle formulations tested was DOPC/LL (3:2). The resultsdemonstrate that at increasing shear rate, the DOPC/LL formulation canbe shear thinning. At 0.014 sec⁻¹, η=412,000 poise. At 0.16 sec⁻¹,η=60,600 poise. In a diffusion moderator, the shear rate isapproximately 10⁻⁴ to 10⁻² sec⁻¹. In a mixer, the shear rate isapproximately 10¹ to 10² sec⁻¹. The ratio of DOPC/LL can be adjusted toachieve an appropriate viscosity.

Example 12

FIG. 8 shows a shear rate effect on a DOPC:NMP vehicle formulation at37° C. The vehicle formulations tested was DOPC/NMP (3:1). The resultsdemonstrate that at increasing shear rate, the DOPC/NMP formulation canbe shear thinning. At 0.024 sec⁻¹, η=310,000 poise. At 9.7 sec⁻¹,η=1,040 poise. The ratio of DOPC/NMP can be adjusted to achieve anappropriate viscosity.

Example 13

FIG. 9 shows the stability of ω-interferon in DOPC:LL suspension at 40°C. The percentage of dimer, oxide and deamide of ω-interferon wasmeasured at 0, 2, and 4 weeks for ω-interferon in DOPC:LL suspension byMeCl₂:Methanol (95:5) or MeCl₂:n-propanol (50:50) extraction. TheDOPC:LL suspension particle at 0 weeks contained 1.63% oxide, 1.45%deamide, 7.94% unknown, and 0.07% dimer. ω-interferon in DOPC:LLsuspension was stable for 4 weeks at 40° C.

Example 14

Table 8 shows ω-interferon recovery from viscous liquid suspensions,DOPC:NMP or DOPC:LL. Assessment of in vitro release rate recovery wasmeasured after adding 6 mg of viscous liquid suspensions to 2 ml ofrelease rate medium (phosphate-buffered 0.8% saline). Release of ω-IFNfrom the suspension into the medium was measured from t=0 days to t=7days. Percent recovery is based on a protein concentration of 1.67 wt %in the viscous liquid suspension formulation. The results indicate thatgreater than 90% soluble ω-IFN is recovered after incubation for sevendays at 37° C.

TABLE 8 ω-Interferon Recovery from Viscous Liquid Suspension Time %Recovery % Recovery (days) NMP:DOPC LL:DOPC 0 88.96 (5.56) Not available7 95.09 (5.3)  91.16 (0.45) % Recovery data is an average of 3 samples(±SD).

Example 15

In the study in Example 14 (Table 8), the DOPC:NMP viscous liquidsuspension showed a slight increase in recovery of soluble ω-interferonfrom t=0 days to 7 days. A further experiment was performed to determinewhether a delay in release of protein to release rate medium was due tothe fact that viscous liquid suspensions do not dissolve or disperse inphosphate-buffered saline (PBS). To compare release rates, ω-interferonconcentration was measured in aqueous solution. n-propanol was added todissolve lipid, and ω-interferon was measured again to determine whetheraddition of non-aqueous liquid solvent result in higher proteinrecoveries.

FIG. 10 shows the effect of n-propanol on recovery of ω-interferon fromDOPC:NMP or DOPC:LL suspensions. The results show an increase in totalω-IFN recovered into an aqueous phase from DOPC:NMP or DOPC:LLsuspensions following treatment with N-propanol. Increased recoveryfollowing N-propanol treatment occurred in both delivery systems, glasscap and spiral DM.

Example 16

Water ingress into model diffusion moderators was measured for viscousliquid formulations, DOPC:LL or DOPC:NMP. See FIG. 11. Measured after 38days, the distance of water ingress into capillary tubes of diffusionmoderators was less than 5 mm for viscous liquid formulations, DOPC:LLor DOPC:NMP. Less water ingress was observed with the DOPC:LLformulation than with the DOPC:NMP formulation. Minimal water ingressinto the device, as shown in FIG. 11, has been shown to be advantageousto protein delivery from the DUROS® osmotic delivery device.

Example 17

Additional solvents in combination with a lipid, e.g., DOPC, are usefulin suspension formulations of viscous liquid compositions for parenteraldrug delivery. Solvents that are useful in a viscous liquid formulationhave hydrophobic character, for example, sesame oil, vitamin E(α-tocopherol), or silicon medical fluid (SMF, polydimethylsiloxane).

Example 18

FIG. 12 shows a measure of average protein released from a deliverydevice based upon piston movement within the device. Based on pistonmovement, delivery of the DOPC:LL viscous liquid formulation is attarget. Volumetric flow rate is consistent for the periods between Day 7to 21 and Day 21 to 35. Target flow rate is 1.5 μl per day. Density ofthe viscous liquid formulation is assumed to be approximately 1 gm/ml.

Example 19

FIG. 13 shows that piston movement in a delivery device correlates tothe average protein released from the device. Release of solubleω-interferon from DOPC:LL (3:2) formulations is closer to target whentarget is adjusted based on x-ray results of the delivery device.Release rate samples were treated with n-propanol. The target is basedon 1.03% soluble ω-interferon in suspension.

Example 20

ω-interferon is stable in DOPC: sesame oil (1.5:1) viscous liquidcomposition for up to four weeks at 40° C. See Table 9. Percentoxidation shows an increase from t=0 weeks to t=4 weeks. Consistency andviscosity of the viscous liquid composition indicates that sesame oilcan be added as a co-solvent with vitamin E (α-tocopherol) incombination with a lipid, e.g., DOPC.

TABLE 9 Stability of ω-interferon in DOPC:sesame oil viscous liquidcompositions % % % % % Monomer Dimer Oxidation Deamidation Unknown Spraydried 99.67 (0.01) 0.23 (0.01) 1.9 (0.39) 2.02 (0.01) 7.17 (0.44)Particle t = 0 99.87 (0.03) 0.14 (0.03) 2.1 (0.17) 1.27 (0.37) 8.72(0.82) SesOil:DOPC t = 2 wks 99.67 (0.02) 0.02 (0.01) 3.78 (0.03) 1.56(0.04) 7.57 (0.56) SesOil:DOPC t = 4 wks 99.85 (0.00) 0.14 (0.01) 4.29(0.13) 2.55 (0.10) 5.59 (0.24) SesOil:DOPC Data is an average of foursamples (±SD).

Example 21

DOPC has been combined with various solvents (1:1 weight ratio) to yielda viscous liquid composition as shown in Table 10. Lipid and solvent aremixed and heated between approximately 65 to 100° C. with continuedmixing. Suitability of various solvents in the composition wasevaluated.

TABLE 10 Analysis of properties of various solvent in combination withlipid, DOPC Solvent Result Action Vitamin E (α-tocopherol) Producesclear gel. Pursue Ethyl oleate Clear, low viscosity gel. Pursue Capryliccapric triglyceride Clear, low viscosity gel. Pursue Vegetable oils WithDOPC, physical (sesame, soy, cottonseed oil) separation seen over time.Poly oxyl 35 castor oil With DOPC, physical (PEG 35 Castor Oil)separation seen over time. Silicone medical fluid (SMF) DOPC not solublein solvent. Poly ethylene glycol 400 (PEG) DOPC not soluble in solvent.Polysorbate 20, 80 DOPC not soluble in solvent.

Example 22

Suspending vehicles comprising DOPC and Vitamin E were prepared atvarious weight ratios and viscosity was measured. FIG. 14 shows thatviscosity increases by two orders of magnitude with a 5% change incomposition. At a ratio of 0.75:1 DOPC:VitE, samples looked thin to theeye in that they flowed fairly easily when the sample vial was tipped onits side. At a ratio of 0.9:1, samples looked thicker than 0.75:1, andthere was still flow when the sample vial was tipped on its side.

Example 23

A performance modifier is added to suspending vehicles of Example 22. Itis desirable to reduce large variation of viscosity due to smallvariations in composition. A viscosity change of less than a factor of10 is obtained over a composition change of 10% DOPC by weight.

Example 24

Suspending vehicles comprising DOPC and Vitamin E were prepared atvarious weight ratios and were exposed to aqueous media. In someexamples, PBS was used as an aqueous medium. In other examples, BovineSerum (adult) Sigma product B2771, lot 29H8401 was used. Samples wereobserved at room temperature at various times from 0 to 24 hours fromthe time that the aqueous media was added to the suspending vehicle.Table 11 shows that stiff phases, for example, gels, are produced uponcontact of the suspending vehicles with aqueous media. Such formation ofstiff phases could lead to plugging of a diffusion moderator of a dosageform, such as a DUROS device.

TABLE 11 Analysis of properties of various suspending vehicles without aperformance modifier upon contact with aqueous media Aqueous Media Added(% by Result: Physical properties Sample (Weight ratios) weight) ofresulting phase DOPC:VitE 0.75:1 10% PBS stiff but pliable DOPC:VitE0.75:1 25% PBS stiff but pliable, excess water DOPC:VitE 0.75:1 50% PBSstiff but pliable, excess water DOPC:VitE 1:1 10% PBS stiff but pliableDOPC:VitE 1:1 25% PBS stiff but pliable, excess water DOPC:VitE 1:1 50%PBS stiff but pliable, excess water DOPC:VitE 0.75:1 10% serum Stiff,pliable, but more crumbly than when PBS is added, excess aqueous phaseDOPC:VitE 0.75:1 25% serum Stiff, pliable, but more crumbly than whenPBS is added, excess aqueous phase DOPC:VitE 0.75:1 50% serum Stiff,pliable, but more crumbly than when PBS is added, excess aqueous phase

Example 25

Suspending vehicles comprising DOPC, Vitamin E, and a performancemodifier were prepared. In some examples, the performance modifier wassesame oil. In one example, the performance modifier was ethyl acetate.PBS was used as an aqueous medium. Samples were observed at roomtemperature at various times from 0 to 24 hours from the time that theaqueous media was added to the suspending vehicle. Table 12 shows thatunlike the suspending vehicles prepared without either sesame oil orethyl acetate, soft phases are produced upon contact of the suspendingvehicles with aqueous media. As such, the addition of sesame oil orethyl acetate will soften gels or the like that result from the additionof aqueous media to suspending vehicles that do not contain aperformance modifier.

TABLE 12 Analysis of properties of various suspending vehicles having aperformance modifier upon contact with aqueous media Aqueous Media Added(% by Result: Physical properties Sample (Weight ratios) weight) ofresulting phase DOPC:VitE 0.75:1 25% PBS, then softer added 10% ethylacetate DOPC:solvent 1.5:1 25% PBS soft phase, very easy to move(Solvent = 75:25 in vial VitE:SesOil) DOPC:solvent 1.5:1 50% PBS softphase, very easy to move (Solvent = 75:25 in vial VitE:SesOil)

Example 26

A suspending vehicle comprising DOPC and Vitamin E was prepared withouta performance modifier according to the following.

Weighed appropriate amount of DOPC in a glass jar. Weighed appropriateamount of Vitamin E directly onto the DOPC. Allowed mixture to incubatein 90° C. oven for 10 minutes. Transferred to Keyence Hybrid mixer. Ahybrid mixer operates by applying a large, continuous, centrifugalforce, produced by combination of the rotation of the material containerand the revolution in a certain radius, removing air bubbles from thematerial while blending its contents. Mixed for 20 minutes in Keyencemixer. Incubated at 37° C. overnight. Heated on 85° C. hotplate for 10minutes.

Mixed by hand with spatula for 5 minutes. Incubated sample in 90° C.oven for 10 minutes. Transferred to Keyence Hybrid mixer. Mixed for 20minutes in Keyence mixer. Heated on 85° C. hotplate for 10 minutes.

Mixed by hand with spatula for 10 minutes. Incubated sample in 90° C.oven for 10 minutes. Transferred to Keyence Hybrid mixer. Mixed for 20minutes in Keyence mixer. Incubated at 37° C. overnight. Heated on 85°C. hotplate for 15 minutes.

Mixed by hand with spatula for 10 minutes. Transferred to Keyence Hybridmixer. Mixed for 20 minutes in Keyence mixer.

Total processing time took ˜3 days to obtain a suspending vehicle thathad DOPC substantially dissolved in Vitamin E.

Example 27

A suspending vehicle comprising DOPC and Vitamin E was prepared with aperformance modifier, for example, ethanol, according to the following.

Weighed equal parts ethanol and DOPC into a test tube. Vortexed mixturefor one minute on highest setting. Allowed mixture to sit for 5 minutesat room temperature. Weighed appropriate amount of Vitamin E into sametest tube. Heated to 100-120° C. while mixing with a spring mixing bladefor 1.5-3 hr under full vacuum. A spring mixing blade is essentially aspring attached to a straight rod.

Total processing time took ˜4 hours to obtain a suspending vehicle thathad DOPC substantially dissolved in a combination of ethanol and VitaminE.

Example 28

A pharmaceutical suspension comprising DOPC, Vitamin E, sesame oil, andω-interferon is prepared. The suspension is subjected to stabilitytesting. It is desirable to obtain pharmaceutical suspensions that areshelf-stable for extended periods of time. The pharmaceutical suspensionremains a homogeneous formulation for at least 3 months at 37° C. Visualobservations of suspension appearance and measurement of drug levelsthroughout the suspension are used to determine that the suspension ishomogenous.

When ranges are used herein for physical properties, such as molecularweight, or chemical properties, such as chemical formulae, allcombinations and subcombinations of ranges and specific embodimentstherein are intended to be included.

The disclosures of each patent, patent application and publication citedor described in this document are hereby incorporated herein byreference, in their entirety.

Those skilled in the art will appreciate that numerous changes andmodifications can be made to the embodiments of the invention and thatsuch changes and modifications can be made without departing from thespirit of the invention. It is, therefore, intended that the appendedclaims cover all such equivalent variations as fall within the truespirit and scope of the invention.

1. A particle formulation for use in a pharmaceutical compositioncomprising a protein or peptide, sucrose, methionine, and citratebuffer.
 2. The particle formulation of claim 1, wherein said protein orpeptide is selected from the group consisting of interferon,erythropoietin, human growth hormone, granulocyte macrophage colonystimulating factor, human growth hormone releasing hormone, insulin,infliximab, and glucagon-like peptide-1.
 3. The particle formulation ofclaim 2, wherein the protein or peptide is glucagon-like peptide-1. 4.The particle formulation of claim 2, wherein the protein or peptide isan interferon.
 5. The particle formulation of claim 4, wherein theinterferon is selected from the group consisting of omega-interferon,alpha-interferon, beta-interferon, and gamma-interferon.
 6. The particleformulation of claim 1, wherein the particle formulation comprises theprotein or peptide, sucrose, methionine, and citrate buffer in a weightratio of 1:2:1:2.15.
 7. The particle formulation of claim 1, whereinparticles of the formulation are made by spray-drying, lyophilization,or supercritical fluid processing.
 8. The particle formulation of claim1, wherein the particle formulation comprises spray-dried particles. 9.The particle formulation of claim 8, wherein the spray-dried particlescomprise particles of about 1 μm to about 10 μm in diameter.
 10. Animplantable osmotic delivery device, comprising: a capsule having afirst chamber containing a viscous liquid pharmaceutical composition anda second chamber containing an osmotic agent, the first chamber havingan opening through which the pharmaceutical composition can be deliveredfrom the first chamber to a location external of the first chamber; amovable piston positioned in the capsule between the first chamber andthe second chamber; a wall of the second chamber comprising a fluidpermeable membrane portion; and an incompressible fluid additive locatedwithin the second chamber and substantially surrounding the osmoticagent; wherein the viscous liquid pharmaceutical composition comprisesthe particle formulation of claim 1 dispersed in a suspending vehicle,and the suspending vehicle comprising a solvent selected from the groupconsisting of benzyl benzoate, lauryl lactate, and lauryl alcohol. 11.The implantable osmotic delivery device of claim 10, wherein the solventis benzyl benzoate.
 12. The implantable osmotic delivery device of claim10, wherein the solvent is lauryl lactate.
 13. The implantable osmoticdelivery device of claim 10, wherein the solvent is lauryl alcohol. 14.The implantable osmotic delivery device of claim 10, wherein thesuspending vehicle further comprises a lipid.
 15. The implantableosmotic delivery device of claim 10, wherein the particle formulationcomprises the protein or peptide, sucrose, methionine, and citratebuffer in a weight ratio of 1:2:1:2.15.
 16. The implantable osmoticdelivery device of claim 10, wherein particles of the formulation aremade by spray-drying, lyophilization, or supercritical fluid processing.17. The implantable osmotic delivery device of claim 10, wherein theparticle formulation comprises spray-dried particles.
 18. Theimplantable osmotic delivery device of claim 17, wherein the spray-driedparticles comprise particles of about 1 μm to about 10 μm in diameter.19. The implantable osmotic delivery device of claim 10, wherein theosmotic agent is a tablet comprising NaCl.
 20. The implantable osmoticdelivery device of claim 19, wherein the incompressible fluid additivecomprises PEG.